Type 2 diabetes is a polygenic disorder characterized by hyperinsulinemia, insulin resistance, and defect(s) in islet secretory function. Obese humans have a high incidence of type 2 diabetes and manifest both hyperinsulinemia and hyperleptinemia. The significance and interaction between insulin and leptin signaling pathways in the context of development of type 2 diabetes in obese humans are not fully understood. In addition to its central effects on appetite control, leptin has been reported to impact peripheral tissues including skeletal muscle, hepatocytes and pancreatic islets. Receptors for leptin are expressed in most tissues in mammals, including the pancreatic islets and recent reports have suggested that leptin can act through some components of the IGF-I/insulin- signaling pathway including IRS-2. To directly address the role of leptin in pancreatic islets, we have created a pancreas-specific knockout of the long form of the leptin receptor (panc-ObRbKO) using a PDX-Cre mouse. Although this approach would delete expression of ObRb in all pancreatic tissues originating from PDX-1, this model has allowed us to study the direct consequences on the endocrine pancreas compared to global effects in the db/db mouse. The broad goals of this proposal are to explore the role of leptin in islet growth during islet compensation to insulin resistance and to dissect the pathways linking leptin signaling with cyclin D2 and growth factor signaling pathways. The availability of the panc-ObRbKOs on a C57Bl/6 background provides us with the critical reagent to immediately begin our studies upon commencement of the Grant period. The data from these experiments will be useful to apply for an R01 application with the long-term goal of understanding the cause(s) of b-cell failure in type 2 diabetes in the context of obesity. The proposed studies are directly in response to the NIH roadmap to investigate the pathophysiology underlying obesity. The specific aims of this proposal are to: define alterations in apoptosis, replication and neogenesis of b-cells from pancreas-specific leptin receptor knockout mice (panc-ObRbKO) and test the hypothesis that cyclin D2 is critical for b-cell proliferation in panc-ObRbKO mice; determine the ability of panc-ObRbKO mice to mount an islet compensatory response, which is normally induced by a high-fat diet; and dissect pathways that link leptin signaling with cyclin D2 in regulation of islet/b-cell growth. The studies outlined in this proposal address an important problem in the western world - the increasing incidence of type 2 diabetes in obese individuals. Using unique genetically engineered mouse models and cell biological techniques we will identify the proteins that are critical for understanding the pathways that are critical for the control of mass of insulin-producing beta-cells. The proposed studies are aimed at the long-term goal of developing therapeutic strategies to prevent or delay the development of diabetes in obese individuals. [unreadable] [unreadable] [unreadable]